Method for the synthesis of 5-hydroxymethylfurfural ethers and their use

ABSTRACT

Method for the manufacture of 5-hydroxymethylfurfural derivatives by reacting a fructose and/or glucose-containing starting material with an alcohol in the presence of a catalytic or sub-stoichiometric amount of solid (“heterogeneous”) acid catalyst. The catalysts may be employed in a continuous flow fixed bed or catalytic distillation reactor. The ethers can be applied as a fuel or fuel additive.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12,282,264, filed Sep. 9, 2008, which is the National Stage ofInternational Application No. PCT/EP2007/002145, filed Mar. 12, 2007,which claims the benefit of European Application No. EP 06075564.2,filed Mar. 10, 2006, the contents of which are incorporated by referenceherein.

FIELD OF THE INVENTION

The present invention relates to a method for the preparation ofderivatives of 5-hydroxymethylfurfural (HMF), in particular etherderivatives of HMF, more in particular to 5-alkoxymethylfurfural ethersand to their application as a fuel or fuel additive.

BACKGROUND OF THE INVENTION

The conversion of sugars or sugar (hexoses) containing biomass into moreeconomically useful compounds is of increasing interest. Current fuelactivities are mainly directed towards ethanol from sugar/glucose.Typically, sucrose and glucose are fermented into ethanol. One glucosemolecule is converted into two molecules of ethanol and two molecules ofCO2. This conversion has drawbacks especially in view of atom economy,the low energy density of ethanol (7.7 kWh/kg or 6.1 kWh/L) and itsrelative low boiling point (78.4 degrees Celsius).

Another application area involves the conversion of sugars such asfructose into HMF in the presence of an acid catalyst has been reported(for example in EP0230250 to Suedzucker or EP0561928 to CEA)). In thiscase HMF is obtained as a highly potential starting material forobtaining bio-based monomer such as furandicarboxylic acid which caninter alia be used as an alternative to terephthalic acid as a monomerfor polyethylene terephthalate type polyesters (Moreau et. al. in Topicsin Catalysis Vol 27, Nos. 1-4, 2004, 11-30 and references citedtherein). When under these conditions sucrose or glucose was used as afeed, no conversion to HMF is observed (Moreau et. al. in Topics inCatalysis Vol 27, Nos. 1-4, 2004, p 13, col 2. line 2-3), which is adistinct disadvantage given the low price and abundant availability ofsucrose and glucose. Only in the presence of DMSO, DMF and DMA (low HMFyields from glucose: Ishida et. al. Bull. Chem. Soc. Jpn 74 2001, 1145)or in a sub- and supercritical mixture of acetone and water (fructose,glucose, sucrose and inulin conversion to HMF in 77%, 48%, 56% and 78%yields respectively: Vogel et. al. Green Chemistry 5, 2003, 280)reasonable HMF yields from starting materials other than fructose wereobtained.

In the current market situation, fructose as feed is undesirable giventhe high price thereof, compared to glucose and/or sucrose. Therefore,so far, no process for the synthesis of HMF has been developed on anindustrial scale.

The synthesis chemistry and applications of HMF are reviewed extensivelyin Lewkowski, ARKIVOC 2001, (i) 17-54; in Gandini, Prog. Polym. Sci. 22,1997, 1203; in Lichtenthaler, C. R. Chimie, 7, 2004, 65 and Acc. Chem.Res. 35, 2002, 728; and Moreau, Topics in Catalysis, 27, 2004, 11.

DE3621517 relates to a process for the synthesis ofalkoxymethylfurfurals and alkyl levulinates from cellulose orlignocelluloses or starch and alcohols. The starting materials areheated briefly (for 1 to 60 minutes) at 170 DEG to 225 DEG C. with anaddition of a strong, catalytically acting acid and, if appropriate, afurther, inert solvent in a pressure apparatus. Alcohols which can beemployed are primary or secondary aliphatic alcohols, preferablymethanol or ethanol. The strong acid used is preferably sulphuric acidat a concentration of 0.5 to 10% (based on the alcohol), if appropriatewith an addition of a metal halide. Lignocellulose-based raw materialsand waste substances, such as wood, wood pulp (cellulose), waste paper,cereal straw, bagasse or the like, can thus be converted intoextractable and distillable organic intermediates. Similar informationis provided by the inventor of this German patent reference in JOURNALOF WOOD CHEMISTRY AND TECHNOLOGY, MARCEL DEKKER, NEW YORK, NY, US—ISSN0277-3813, Vol: 8, Nr. 1, Page(s): 121-134 (1988). On the other hand,the process produces primarily alkyl levulinates; the production of HMFethers using the sulphuric acid (a non-solid) is rather poor (themaximum yield of an HMF-ether reported in the 11 examples of DE621517 is5.3% and 2.7% in Garves' scientific paper).

DE635783 describes a process for the preparation ofalkoxymethylfurfurals and alkyl levulinate esters. The acid used isgaseous hydrochloric acid, a non-solid catalyst. As is illustrated inthe examples of this German patent, the product prepared from glucose,saccharose, or starch is mostly the alkyl levulinate ester (the maximumyield of EMF ether reported is 6.4%.

Tyrlik et al describes the “Selective dehydration of glucose tohydroxymethylfurfural and a one-pot synthesis of a 4-acetylbutyrolactonefrom glucose and trioxane in solutions of aluminium salts” inCARBOHYDRATE RESEARCH, ELSEVIER SCIENTIFIC PUBLISHING COMPANY.AMSTERDAM, NL—ISSN 0008-6215, Vol: 315, Nr. 3-4, Page(s): 268-272(1999). The acidic catalyst under the reaction conditions illustrated inthis article is a homogeneous catalyst. The yield of thealkoxymethylfurfural is rather poor (the maximum yield of HMF+HMF-ethercombined is 14%.

Moye et al describes the “Reaction of ketohexoses with acid in certainnon-aqueous sugar solvents” in JOURNAL OF APPLIED CHEMISTRY, SOCIETY OFCHEMICAL INDUSTRY. LONDON, GB, Vol: 16, Nr. 7, Page(s): 206-208 (1966).HMF is made using various acidic catalysts from fructose, sorbose,kestose and inulin (a group of polysaccharides based on fructose with aterminal glucose group). No experiments were done with glucose. The HMFyields reported from fructose (Table I) appear high, but do no concernisolated HMF, but rather calculated values on the basis of UV analysis.The yield of the ethers of 5-hydroxymethylfurfural is unknown, given theindication that the furfuryl alcohols were very unstable to acid andreadily polymerised at room temperature, it is thus rather evident thatthe yield of such ethers is rather insignificant.

In the paper by Tarabanko et al, on the “Preparation of butyl levulinateby the acid-catalyzed conversion of sucrose in the presence o butanol”,published in “Khimiya Rastitel'nogo Syrýa (2004), (2), 31-37, thepulse-flow process of the acid-catalyzed conversion of sucrose in thetwo-phase water-butanol system is studied. 5-HMF and levulinic acid wereobtained as the main products, using a solution of sulphuric acid andsodium hydrosulfate as catalyst. The conversion of glucose into analkoxymethylfurfural is not disclosed. A similar conclusion may be drawnon the second article by the same author: “Catalyzed carbohydratedehydration in the presence of butanol at moderate temperatures”,published in “Khimiya Rastitel'nogo Syrýa (2002), (2), 5-15

RU2203279 relates to the synthesis of 5-hydroxymethylfurfural ethersfrom sucrose. The end product is synthesized by dehydration of sucroseor fructose in a biphasic system in the presence of sodium bisulfite ormixture of sodium bisulfite and sulfuric acid as catalyst and aliphaticalcohols as alkylating agent under normal pressure. In a biphasicsystem, these catalysts are homogeneous. Another distinguishing featureof this process is the use of sucrose or fructose as the parent reagent.

Finally, WO9967409 relates to a “METHOD OF TREATING BIOMASS MATERIAL”wherein hemicellulosic and cellulosic components in biomass material arehydrolyzed in a single-stage digester by using a dilute mineral acidsuch as sulfuric acid or nitric acid, at a temperature above 200 DEG C.and a residence time of less than ten minutes. The hemicellulosiccomponents are converted to monosaccharides selected from the groupconsisting of pentoses and hexoses and the cellulosic components areconverted to glucose. In addition, organic acids, furfural,5-hydroxymethylfurfural, acid-soluble lignin, levulinic acid and otherproducts are produced. The acid used is sulphuric acid or nitric acid,as a dilute aqueous solution, i.e., a homogeneous catalyst. The productstream is one of C6 and C5 sugars combined with furfural, HMF, levulinicacid, ASL and other extracted organics. The preparation of alkoxy ethersof HMF is not disclosed.

Concluding, the current methods for the synthesis of HMF mostly startfrom fructose and typically do not give high yield, partly attributableto the instability of HMF under the acidic reaction conditions. In mostacid-catalysed water-based reactions, the further reaction to levulinicacid and humins has been reported, making this a less attractivealternative.

The present inventors have set out to overcome these disadvantages.

SUMMARY OF THE INVENTION

Surprisingly, the inventors have found that the conversion ofhexose-containing starting material, in particular fructose and/orglucose-containing starting material and more particularglucose-containing material that may be derived from biomass in thepresence of a catalytic or sub-stoechiometric amount of acid in thepresence of an alcohol with or without the presence of one or moreadditional diluents leads to the formation of the correspondingHMF-ether in good yield and selectivity.

Thus, the invention pertains to a method for the manufacture of5-alkoxymethylfurfural ethers by reacting a fructose and/orglucose-containing starting material with an alcohol in the presence ofa catalytic or sub-stoechiometric amount of acid catalyst.

It was found that this in situ formation and derivatisation of HMFprevents the occurrence of the onward and undesired reaction towards theabove-mentioned levulinic acid and humins, thus leading to an efficientprocedure for the conversion of fructose and/or glucose-containingmaterial into HMF derivatives.

The energy density of 5-ethoxymethylfurfural (EMF), the ether resultingfrom reaction of HMF with (bio)ethanol, can be calculated. Taking intoaccount stoeichiometry and a calculated enthalpy of formation usingincrement tables of 502.32 kJ/mole, the reaction enthalpy can becalculated as 3854.76 kJ/mol, leading to an energy density of 7.0 kWh/kgor 8.7 kWh/L. This is as good as regular gasoline (12.7 kWh/kg, 8.8kWh/L) and diesel ((11.7 kWh/kg, 9.7 kWh/L) and significantly higherthan ethanol (7.7 kWh/kg, 6.1 kWh/L). This high energy density of EMF,the fact that these HMF derivatives can now be obtained in high yields,in one step, from very cheap hexose or hexose-containing startingmaterials such as sucrose and glucose, and as these ethers are, incontrast to HMF, liquids at room temperature, make these veryinteresting fuels or fuel additives.

In certain embodiments, the alcohol is selected from the groupconsisting of primary (un)branched aliphatic alcohols. In certainpreferred embodiments, the alcohol is selected from the group consistingof primary C1-C5 (un)branched aliphatic alcohols, preferably methanol,ethanol, 1-propanol, 2-hydroxymethyl-propanol, 1-butanol. Morepreferable are methanol and/or ethanol. The resulting (m)ethyl ether((m)ethoxymethylfurfural, MMF or EMF) has a high energy content and maydirectly be used as a fuel additive as an alternative for MTBE or as afuel. Mixtures of alcohols may also be employed. Ethanol is the mostpreferred alcohol in the method of the present invention as the ethanolthat is used can also be derived from biomass or glucose-containingmaterial (bio-ethanol).

The acid catalyst in the method of the present invention can be selectedfrom amongst solid (halogenated) organic acids, inorganic acids, salts,Lewis acids, ion exchange resins and zeolites or combinations and/ormixtures thereof, including combinations and/or mixtures thereof with ahomogenous catalyst. The expression “solid” is here used in the ordinarymeaning of the word as being solid during the reaction. Another commonexpression for solid catalysts is “heterogeneous” catalyst. The acid maybe a protonic, Brønsted or, alternatively, a Lewis acid. In certainembodiment, the acid may be organic or inorganic. In certainembodiments, the organic acid can be selected from amongst oxalic acid,levulinic acid, maleic acid or para-toluenesulphonic acid. In certainembodiments, the inorganic acid can be selected from amongst phosphoricacid, sulphuric acid, hydrochloric acid, hydrobromic acid, nitric acid,hydroiodic acid, optionally generated in situ.

In certain embodiments, the inorganic acid is selected form the group ofsulphuric acid, phosphoric acid, hydrochloric acid, nitric acid. Incertain embodiments, the salt can be one of (NH4)2SO4/SO3, ammoniumphosphate, triethylamine phosphate, pyridinium salts, pyridiniumphosphate, pyridinium hydrochloride/hydrobromide/perbromate, DMAP,aluminium salts, Th and Zr ions, zirconium phosphate, Cr-, Al-, Ti-,Ca-, In-ions, ZrOCl2, VO(SO4)2, TiO2, V-porphyrine, Zr-, Cr-,Ti-porphyrine. In certain embodiments, the Lewis acid can be one ofZnCL2, AlCl3, BF3. In certain embodiments, the ion exchange resins canbe one of Amberlite, Diaion, levatit. In certain embodiments, it ispreferred that the acid catalyst is a solid catalyst that may beselected form the group consisting of acid resins, natural clay mineral,zeolites, supported acids such as silica impregnated with mineral acids,heat treated charcoal, metal oxides, metal sulfides, metal salts andmixed oxides and mixtures thereof. In certain embodiments, mixtures orcombinations of acid catalysts can be used.

The temperature at which the reaction is performed may vary, but ingeneral it is preferred that the reaction is carried out at atemperature from 50 to 300 degrees Celsius, preferably from 125 to 250,more preferably from 175 to 225 degrees Celsius.

In general, temperatures higher than 300 are less preferred as theselectivity of the reaction as many by-products occur, inter aliacaramelisation of the sugar. Performing the reaction below the lowesttemperature is also less preferable because of the slow reaction speed.

The fructose and/or glucose-containing starting material can be selectedfrom a wide variety of feeds. In general any feed with a sufficient highfructose or glucose content can be used. It is preferred that thefructose and/or glucose-containing starting material is selected fromthe group of starch, amylose, galactose, cellulose, hemi-cellulose,glucose-containing disaccharides such as sucrose, maltose, cellobiose,lactose, preferably glucose-containing disaccharides, more preferablysucrose or glucose.

The catalyst can be added to the reaction mixture in an amount varyingfrom 0.01 to 40 mole % drawn on the fructose or glucose content of thefructose and/or glucose-containing starting material preferably from 0.1to 30 mole %, more preferably from 1 to 20 mole %.

In certain embodiments, one or more solvents or diluents may be added,in general to aid the dissolution of the glucose containing material oras a diluent. The solvent may be selected form the group consisting ofwater, sulfoxides, preferably DMSO, ketones, preferably methylethylketone, methylisobutylketone and acetone or mixtures of two or moreof the above solvents.

In certain embodiments, the ratio of alcohol/solvent is from 50 to 0.1,preferably from 20 to 1, more preferably from 10 to 2.

Higher amounts of alcohol may have the result that the reaction is tooslow due to the limited solubility (hence availability of the startingmaterial), whereas too much solvent in the system may lead to a too highdilution, which in both cases are less preferred results. One of thepossible solvents is water.

In certain embodiments, the method can be performed in a continuous flowprocess. In such method, the residence time of the reactants in the flowprocess is between 0.1 second and 10 hours, preferably from 1 second to5 hours, more preferably from 1 minute to 1 hour.

In certain embodiments the continuous flow process is a fixed bedcontinuous flow process or a reactive (catalytic) distillation processwith preferably a solid (“heterogeneous”) acid catalyst. To initiate orregenerate the heterogeneous acid catalyst or to improve performance, aninorganic or organic acid may be added to the feed of the fixed bed orreactive distillation continuous flow process. In a fixed bed process,the liquid hourly space velocity (LHSV) can be from 1 to 1000,preferably from 5 to 500, more preferably from 10 to 250 and mostpreferably from 25 to 100.

As explained above, the application of the products of the method of thepresent invention, i.e. the ethers, is in the use as a fuel or fueladditive and as precursor for the manufacture of2,5-di(hydroxymethyl)furan, furan-2,5-dicarboxylic acid,2-hydroxymethylfuran-5-carboxylic acid,2,5-(dihydroxymethyl)tetrahydrofuran, which can be used as monomers in apolymerisation process, optionally after conversion of the diol to adiamine. See for a review Moreau, Topics in catalysis, 2004, 27, 11-30.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Plot of a) conversion, b) selectivity to furan derivativesversus space velocity. 180 C, heterogeneous catalysts, reaction mediumwater. Catalyst 1: □; Catalyst 2: ▪ Catalyst 3: * Catalyst 4: .

FIG. 2. Plot of a) conversion, b) selectivity to furan derivativesversus space velocity. 180 C, heterogeneous catalysts, reaction medium88.7% ethanol. Catalyst 1: □; Catalyst 2: ▪ Catalyst 3: * Catalyst 4: .

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Examples Apparatus

Continuous parallel flow reactor system consisting of four quartzreactors inserted in a silver heating block; temperature and flowregulators and three HPLC pumps. Two of the pumps deliver the liquid tothe reactors and third one is employed to dilute the reaction productsprior to collection.

Analytical Method

The reaction products were quantified with the aid of HPLC-analysis withan internal standard (saccharine, Sigma Aldrich). A Merck-Hitachi L7000chromatograph, equipped UV and RI detectors, was used. Stationary phasewere reverse phase C18 (Sunfire 3.5 m, 4.6×100 mm, Waters) and cationexchange (SupelcogelH, 4.6×300 mm, SigmaAldrich) columns connected inseries. A gradient elution at a constant flow 0.6 ml/min and temperature60° C. was used according to the following scheme.

Time (min) 0.2% TFA (aq) Methanol Acetonitrile 0 90.0 7.0 3.0 10 90.07.0 3.0 11 80.0 0.0 20.0 15 80.0 0.0 20.0 16 90.0 7.0 3.0 21 90.0 7.03.0

General Procedure

A 1.25 wt % solution of glucose (99.7% Sigma Aldrich) in water or 88.7%ethanol was flowed through a fixed bed (200 l) of a solid(“heterogeneous”) catalyst at 180° C. Flow rates were chosen such toachieve a space velocity 0.25 or 0.5 min⁻¹, i.e. contact time 2 or 4min. Liquid coming out of the reactors was diluted by a mixture of waterand ethanol (50:50) to prevent tubing blockages.

Catalysts Tested:

Catalyst 1 Zeolite beta SAR25 (CBV Zeolyst) Catalyst 2 Zeolite Y highSAR (CBV Zeolyst) Catalyst 5 Mordenite H SAR 90 (CBV Zeolyst) Catalyst 7Zeolite Y SAR 5.17 (CBV Zeolyst)

Contact time and space velocity were calculated as follows:

Sv=Fr _(feed) /V _(cat)

Sv space velocity (min⁻¹)Fr_(feed) flow rate feed (ml/min)/V_(cat) catalyst volume (ml)

t _(c)=1/Sv

t_(c) contact time (min)

Conversion of substrate, selectivity and yield of furan derivatives werecalculated according to the following formulae:

X=100m* _(r substrate) /m _(0 substrate)

X conversion (%)m_(r substrate) amount of reacted substrate (mg)m_(0 substrate) amount of substrate in feed (mg)

S _(compound)=100*n _(r substrate) /n _(0 substrate)

S_(compound) selectivity to compound (%)n_(r substrate) moles of substrate reactedn_(0 substrate) moles of substrate in feed

Yield=100*n _(product) /n _(0 substrate)

Yield yield (%)n_(product) moles of product formed

Catalysts Tested:

Catalyst 1 Zeolite beta SAR25 (CBV Zeolyst) Catalyst 2 Zeolite Y highSAR (CBV Zeolyst) Catalyst 3 Mordenite H SAR 90 (CBV Zeolyst) Catalyst 4Zeolite Y SAR 5.17 (CBV Zeolyst)

Reactions in Water.

FIG. 1 a) and b) show that a conversion achieved for the catalyststested was 76% (Zeolite beta). This catalyst gave 7% selectivity to HMFand EMF.

Zeolite Y with high SAR presented 9% selectivity to furans at 20%conversion. Y zeolite with low SAR (catalyst 4) shows selectivity of 4%at very low conversion. Mordenite presented both reduced activity andselectivity to furan derivatives.

HMF was a main furan found in the reaction mixture.

Reactions in Ethanol.

With the use of Zeolite beta about 4% selectivity to HMF and EMF wasachieved at 17% conversion at a low space velocity. For the othercatalysts tested, the conversion developed initially to more than 20%and the selectivity was in the range between 1 and 3%.

The predominant furan derivative was the desired EMF.

DATA Fructose+Ethanol with Solid Acid Catalyst 1fructose conc 55.5 mmol/L; 90% EtOH

fructose conversion Y (HMF) Y (EMF) S (HMF) S (EMF) Restime/s % % % % %10 42 2 9 5 21 30 76 3 24 4 32 60 93 1 35 1 38 120 98 1 37 1 38DATA Glucose+Ethanol with Solid Acid Catalyst 1glucose conc 55.5 mmol/L; 90% EtOH

glucose conversion Y (HMF) Y (EMF) S (HMF) S (EMF) Restime/s % % % % %60 73 2 23 3 32 180 92 1 23 1 25 300 97 1 24 1 25 600 98 1 22 1 22DATA Sucrose+Ethanol with Solid Acid Catalyst 1sucrose conc 27.8 mmol/L (55.5 mmol/L C6H12O6); 90% EtOH

Glu + fru Conversion Y (HMF) Y (EMF) S (HMF) S (EMF) Restime/s % % % % %60 86 4 22 5 26 180 96 3 26 3 27 300 98 3 28 3 29 600 99 2 27 2 27

Engine Test

In a small-scale model diesel engine, comparative testing is performedwith normal commercial diesel as a fuel and the same commercial dieselto which samples of 1 wt. %, 2 wt. %, 3 wt. %, 5 wt %, and 10 wt. % HMFor EMF are added, respectively. The diesel samples with HMF are lesshomogenous on visual inspection (solid particles remain visible,flocculation) and above 5 wt. % HMF, a solid deposit is sometimesobserved. EMF is added as a liquid and does not yield any mixing orflocculation problems. The engine is run stationary with a set volume(100 mL) of fuel until empty. HMF containing fuels run less regular,whereas EMF containing fuels run at a regular pace and for a longerperiod (up to 15%). On visual inspection of the engine, EMF providesless visual contamination.

1.-17. (canceled)
 18. Use of 5-alkoxymethylfurfural, preferably5-methoxy-methylfurfural or 5-ethoxy-methylfurfural as a fuel or as afuel additive.
 19. A method for the manufacture of ethers of5-hydroxymethylfurfural by reacting a fructose-containing startingmaterial with an alcohol in the presence of a catalytic orsub-stoichiometric amount of an acid catalyst, wherein water is presentas solvent in addition to the alcohol, and wherein the method isperformed in a continuous flow process at a temperature of 125 to 300°C.
 20. The method as claimed in claim 19, wherein the temperature rangesfrom 175 to 300° C.
 21. The method according to claim 19, wherein thealcohol is selected from the group consisting of primary branched orunbranched aliphatic alcohols.
 22. The method as claimed in claim 19,wherein the acid catalyst is selected from the group consisting oforganic acids and halogenated organic acids, inorganic acids, salts,Lewis acids, ion exchange resins, zeolites or mixtures and/orcombinations thereof.
 23. The method according to claim 19, wherein theacid catalyst is a heterogeneous catalyst.
 24. The method according toclaim 19, wherein the acid catalyst is a homogenous catalyst.
 25. Themethod according to claim 19, wherein the temperature ranges from 125 to250° C.
 26. The method according to claim 25, wherein the temperatureranges from 175 to 225° C.
 27. The method according to claim 19, whereinthe ratio of alcohol/water-solvent is from 50 to 0.1.
 28. The methodaccording to claim 19, wherein the residence time in the flow process isbetween 0.1 second and 10 hours.
 29. The method as claimed in claim 28,wherein the residence time in the flow process is from 1 minute to 1hour.
 30. The method according to claim 19, wherein the continuous flowprocess is a fixed bed continuous flow process.
 31. The method accordingto claim 30, wherein the continuous flow process is a reactivedistillation or a catalytic distillation process.
 32. The methodaccording to claim 30, wherein the fixed bed comprises a heterogeneousacid catalyst.
 33. The method according to claim 30, wherein in additionto a heterogeneous acid catalyst, an inorganic or organic acid catalystis added to the feed of the fixed bed or catalytic distillationcontinuous flow process.
 34. The method according to claim 30, whereinthe liquid hourly space velocity (LHSV) is from 1 to 1000.